Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials

Abstract

Cetuxiamb, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the efficacy of combined therapies of cetuximab and different chemotherapy regimens remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and toxicity of adding cetuximab to oxaliplatin-based or irinotecan-based chemotherapeutic regimens for the treatment of patients with mCRC with wild-type/mutated KRAS tumors. Randomized controlled trials (RCTs), published in Pubmed and Embase were systematically reviewed to assess the survival benefits and toxicity profile mCRC patients treated with cetuximab plus chemotherapy. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicities. Results were expressed as the hazard ratio (HR) with 95 % confidence intervals (CI). Pooled estimates were generated by using a fixed-effects model or a randomized-effects model, depending on the heterogeneity among studies. A total of 12 trials involving 6,297 patients met the inclusion criteria and were included in this meta-analysis. All patients were administered oxaliplatin-based or irinotecan-based chemotherapy with or without cetuximab. Pooled results showed that the addition of cetuximab did not significantly improve the OS (HR = 0.99, 95 % CI = 0.89-1.09; Z = 0.28, P = 0.78) or PFS (HR = 0.94, 95 % CI = 0.81-1.10; Z = 0.76, P = 0.49), but did improve ORR (RR = 1.34, 95 % CI = 1.08-1.65; Z = 2.72, P = 0.00), when compared with chemotherapy alone. Subgroup analysis showed the highest PFS benefit in patients with wild-type KRAS tumors (HR = 0.80, 95 % CI = 0.65-0.99; Z = 2.1, P = 0.04) or wild-type KRAS/BRAF tumors (HR = 0.64, 95 % CI = 0.52-0.79; Z = 4.15, P = 0.00). When combined with cetuximab, irinotecan-based chemotherapy was significantly associated with prolonged PFS (HR = 0.79, 95 % CI = 0.66-0.96; Z = 2.36, P = 0.02) for all patients with differing gene-status. The incidence of grade 3/4 adverse events, including skin toxicity, diarrhea, hypertension, anorexia, and mucositis/stomatitis, was slightly higher in the combined therapy group than in the chemotherapy-only group. Based on the current evidence, the addition of cetuximab to chemotherapy significantly improves the PFS in patients with wild-type KRAS or wild-type KRAS/BRAF tumors as well as the ORR in all patients. In addition, irinotecan-based combination therapy showed a beneficial effect on the PFS in all patients. These findings confirm the use of cetuximab in combination with chemotherapy for the treatment of patients with mCRC with wild-type KRAS tumors. Further multi-center RCTs are needed to indentify these findings.

A prospective Phase II study to examine the relationship between quality of life and adverse events of first‐line chemotherapy plus cetuximab in patients with KRAS wild‐type unresectable metastatic colorectal cancer: QUACK trial

“…With respect to the third clinical question, influence of AEs other than skin toxicity reactions on HRQOL was also examined by our planned analysis. The addition of cetuximab to the standard chemotherapy for mCRC sometimes exacerbates AEs, including mucositis/stomatitis, decreased appetite, or diarrhea . However, lack of data regarding the impact of these AEs on HRQOL has hindered personalized decision‐making based on the patient's perspective.…”

“…The present study demonstrated that mucositis/stomatitis is a clinically relevant detrimental factor impacting HRQOL, both throughout observation period of 8 and 24 weeks. Mucositis/stomatitis is a common AE of cancer therapy, and the addition of cetuximab enhances chemotherapy‐induced mucositis/stomatitis independent of the chemotherapy backbone via the inhibition of the regenerative and protective effects of the healing process . Of note, mucositis/stomatitis of grade ≥2 will lead to a lower relative dose intensity.…”

“…To date, there have been few prospective assessments investigating HRQOL and skin toxicity . In addition, the previous analyses that have evaluated skin toxicity have not examined the association between HRQOL and all other AEs, including severe symptoms mostly caused by the concomitant chemotherapies . In this respect, a comprehensive examination of the adverse effect on HRQOL is needed to clarify the proper use of anti‐EGFR ab together with the standard chemotherapy for mCRC patients with RAS wild‐type tumors.…”

Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors

“…Cetuximab and panitumumab when combined with chemotherapy both significantly increase the risk of developing mucositis of any grade compared to chemotherapy alone [77-79, 81, 82, 130, 131] (Table 2), with a relative risk of high-grade (≥3) Extensive resection is solely indicated in cases of extended necrosis. a Basic oral care: see Table 3 b Dietary recommendations: frequent drinks between meals, maintaining good oral hygiene, chewing slowly, diversifying and favoring foods for which flavor is not too distorted, and further enhancing the flavor of food using seasonings and flavorings, consuming cold foods, and avoiding overly fragrant foods mucositis ranging from 2.69 [131] to 3.44 [130].…”

Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis

“…The intratumoral heterogeneity in patients could lead to the resistant affects in clinical curative and the difficulty in a target for passive treatment regimens. There have been reported that the intratumoral heterogeneity in EGFR mutation status had recently been described and ranged from 13.9% to 27% in some studies 40, 41. Also, David Malka study 17 is the first and the only to assess the activity of chemotherapy with or without Cetuximab in non-Asian patients with BTC.…”